Rotigotine is the International Non-Proprietary Name (INN) of the compound (−)-5,6,7,8-tetrahydro-6-[propyl-[2-(2-thienyl)ethyl]-amino]-1-naphthalenol having the structure shown below

Two crystalline forms of rotigotine are presently known: polymorphic form I and polymorphic form II (WO 2009/068520). They can be differentiated by their respective physicochemical parameters, i.e. differing powder X-ray diffraction spectra, Raman spectra and melting points. At room temperature, the crystalline polymorphic form II is more stable than form I, which in turn is more stable than the amorphous form of rotigotine.
Rotigotine is a non-ergolinic D1/D2/D3 dopamine agonist that resembles dopamine structurally and has a similar receptor profile but a higher receptor affinity.
In contrast to other non-ergolinic dopamine agonists, rotigotine has significant D1 activity, which may contribute to a more physiological action.
In contrast to ergolinic compounds, rotigotine has a very low affinity for 5 HT2B receptors and thus a low risk of inducing fibrosis.
Actions on non-dopaminergic receptors (such as 5-HT1A agonism and A2B antagonism) may contribute to other beneficial effects, such as antidyskinetic activity, neuroprotective activity and antidepressive effects.
Rotigotine is disclosed as active agent for treating patients suffering from Parkinson's disease (described in WO 2002/089777), Parkinson's plus syndrome (described in WO 2005/092331), depression (described in WO 2005/009424) and the restless-legs syndrome (described in WO 2003/092677) as well as for the treatment or prevention of dopaminergic neuron loss (described in WO 2005/063237) and treatment of pain (PCT/EP2007/005381).
Known pharmaceutical compositions containing rotigotine comprise a transdermal therapeutic system or patch (TTS) (described inter alia in WO 99/49852), a depot form (described in WO 02/15903), an iontophoretic device (described in WO 2004/050083) and an intranasal formulation (described in WO 2005/063236).
To date, various TTS for the administration of amine functional drugs, such as rotigotine and many others, have been described.
WO 94/07468 discloses a TTS containing rotigotine hydrochloride as active substance in a two-phase matrix, which is essentially formed by a hydrophobic polymer material as the continuous phase and a disperse hydrophilic phase contained therein and mainly containing the drug and hydrated silica. The silica is said to enhance the maximum possible loading of the TTS with the hydrophilic salt. Moreover, the formulation of WO 94/07468 usually contains additional hydrophobic solvents, permeation promoting substances, dispersing agents and, in particular, an emulsifier, which is required to emulsify the aqueous solution of the active component in the lipophilic polymer phase. A TTS prepared by using such a system has been tested in healthy subjects and Parkinson's patients. However, no satisfactory drug plasma levels were achieved.
Various further TTS have been described in WO 99/49852. Various further transdermal therapeutic systems have been described in WO 99/49852. The TTS used in this patent application comprise a backing layer, inert with respect to the constituents of the matrix, a self-adhesive matrix layer containing an effective quantity of rotigotine or rotigotine hydrochloride and a protective film which is to be removed before use. The matrix system is composed of a non-aqueous polymer adhesive system, based on acrylate or silicone.
Further TTS for the delivery of rotigotine are for example disclosed in EP 1 256 339 and in WO 2004/012730. These systems utilize a mixture of at least one high tack and at least one medium tack amine-compatible silicone pressure sensitive adhesive as the main adhesive components of the self adhesive matrix. They provide for better flux rates and sufficient rotigotine plasma levels.
Despite the existence of TTS comprising rotigotine in the prior art, there remains room for improvement in such TTS, and in processes for making them.
Crucial pharmaceutical aspects of the TTS are the drug release profile, distribution of the drug within the patch, drug solubility in the matrix, drug and/or patch stability, adhesiveness of the patch to the skin, smooth and complete removability of the patch from the skin.
As these parameters are influencing each other it is difficult to develop a new patch just by amending one parameter.
Recently, it has been found that the systems as described above unfortunately show long-term stability problems. If rotigotine crystals are formed in the self adhesive matrix during long term storage, crystal growth can lead to reduced release rates of rotigotine with the risk eventually falling below the specified values.
Due to the occurrence of a new polymorphic form (form II) of the drug substance rotigotine crystal formation on the commercialized patches can take place. An attempt to modify the manufacturing process resulted only in very limited success. These patches still require cold storage until administration to the skin. This results inter glia in a more complicated application instructions for the rotigotine patch, like that the cooled drug product should be taken out of the refrigerator at least 1 hour before application and the adhesive on the patch has to be warmed up when the patch is applied
In general, it is well known in the art that stabilizing the amorphous state of a drug substance in a pharmaceutical dosage form including transdermal systems can be very difficult, if as in the case of rotigotine, the amorphous form is only metastable and easily converts into crystals. In such a case, the self adhesive matrix as a whole represents a metastable solid dispersion.
It is, therefore, an object of the present invention to provide a TTS comprising rotigotine which does not exhibit the above described drawbacks. In particular, the TTS should display an appropriate drug release profile combined with adequate stability and should be stable at room temperature.